EP2374003B1 - Verfahren zur behandlung, prognosebeurteilung und erkennung von brustkrebs - Google Patents

Verfahren zur behandlung, prognosebeurteilung und erkennung von brustkrebs Download PDF

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EP2374003B1
EP2374003B1 EP10700222.2A EP10700222A EP2374003B1 EP 2374003 B1 EP2374003 B1 EP 2374003B1 EP 10700222 A EP10700222 A EP 10700222A EP 2374003 B1 EP2374003 B1 EP 2374003B1
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nts
ntsr1
expression
patients
cells
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EP2374003A1 (de
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Patricia Forgez
Anne Gompel
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Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris 5 Rene Descartes
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Universite Paris 5 Rene Descartes
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/085—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being neurotensin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/44—Multiple drug resistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to methods for the treatment, the prognostic assessment and the detection of breast cancer.
  • DCIS ductal carcinoma in situ
  • Most of these cases were diagnosed by mammography.
  • High quality mammography is capable of finding a range of asymptomatic non-invasive lesions that cannot be palpated. These are often smaller, of lower nuclear grade, and show much subtler changes than the lesions detected with less advanced mammographic equipment in the past.
  • Technically good mammography requires exceptional attention to detail. The need for expert radiological interpretation cannot be overemphasised. The most common mammographic finding is microcalcifications, but some lesions may present as masses or architectural distortions with or without microcalcifications.
  • Breast Magnetic resonance imaging (MRI) has been approved by the U.S.
  • MRI Food and Drug Administration
  • FDA Food and Drug Administration
  • MRI is useful for staging breast cancer, determining the most appropriate treatment, and for patient follow-up after breast cancer treatment. Because MRI is more sensitive than mammography, it can help detect cancer that may be missed by mammography. However, because this increased sensitivity can also lead to false positive results, which requires breast biopsy procedures, the American Cancer Society does not recommend MRI for all women.
  • NTS Neurotensin
  • Typical physiological functions for NTS include stimulation of pancreatic and biliary secretions, inhibition of small bowel and gastric motility, and facilitation of fatty acids translocation.
  • NTS was equally reported in functions linked specifically to neoplastic progression, including proliferation of the pancreas, prostate, colon, and lung cancer cells. We have previously described a potential role of NTS in breast tumor progression ( Souaze et al (2006) Cancer Res. 66:6243-6249 ).
  • NTS peripheral functions are mediated through its interaction with NTSR1 (High affinity neurotensin receptor 1).
  • NTSR1 High affinity neurotensin receptor 1
  • phosphatidyl inositols are hydrolyzed leading to Ca 2+ mobilization and PKC, ERK1/2, RhoGTPases, NFkappa-B, and focal adhesion kinase (FAK) activation.
  • FKA focal adhesion kinase
  • WO 03/093828 provides assays for the identification of compounds useful in the treatment or prevention of cancer diseases.
  • WO 2005/090603 discloses methods for detecting non-small cell lung cancer using differentially expressed genes KIF11, GHSRlb, NTSR1, and FOXM.
  • the present invention relates to a method of determining the prognosis of a subject suffering from breast cancer, comprising the step of measuring the level of expression of NTRS1 in breast cancer cells obtained from said subject.
  • measuring the level of expression of NTRS1 it is meant measuring the percent of the breast cancer cells expressing NTRS1.
  • a high NTRS1 expression (such as at least 50% of percent or at least 60%, or at least 70% or at least 80% of the breast cancer cells express NTRS1) is associated with a worse prognostic, i.e. a lowest survival rate.
  • NTSR1 expression may be measured for example by RT-PCR or immunohistochemistry performed on a sample obtained by biopsy.
  • the NTSR1 is quantitated in the cancerous cells.
  • the present invention also enables the evaluation of the risk of recurrence of a subject which has been surgically treated and subsequently received the appropriate treatment (such as radiotherapy, chemotherapy and/or hormonal therapy).
  • a method of prognosis according to the invention may be used in combination with any other methods already used for the prognostic assessment of breast cancer, including stage, demographic and anthropometric parameters, results of routine clinical or laboratory examination, including size of the tumor, histoprognostic grading, hormone receptors, oncotype, mammoprint, uPA/PAI-1...
  • Figure 1 Neurotensin expression in normal breast tissue.
  • NTS immunohistochemistry was performed on IDCs, ductal (1) and invasive (2) components, magnification 200X for (1) and 400X for (2).
  • B NTS and NTSR1 transcripts in IDCs. One ⁇ g of total RNA from 11 patients with IDCs were reverse-transcribed, and specific PCR was performed for NTS, NTSR1 receptor, or GAPDH (control). The SBR grade is indicated below each line.
  • Figure 5 Planar images of female nude mice grafted with NTS-h cells. Injected with a DTPA( 111 In)-NTS-analogue
  • Acquisition periods were from 0 to 60 min for the time point at 1h, and 45 min for the three points at 5, 24 and 30 h.
  • P Positive estrogen receptor [n/number of cases studied] 24/27 12/20 0.049
  • Tumor size (cm) [number of cases studied] 28 20 [mean ⁇ SD] 2.08 ⁇ 1.15 2.37 ⁇ 1.16
  • SBR grade [number of cases studied] 28 20 1 14 3 2 12 10 3 2 7 0.011
  • NTS Neurotensin
  • NTSR1 High affinity neurotensin receptor 1
  • IDCs Invasive Ductal Carcinomas
  • SBR grade Scarff-Bloom-Richardson grade
  • ER estrogen receptor
  • PR progesterone receptor
  • HBEC human breast epithelial cells.
  • NTS normal human breast tissue and in invasive ductal breast carcinomas
  • IDCs invasive ductal breast carcinomas
  • NTS expression in normal epithelial breast cells is regulated by estradiol.
  • NTS is also expressed in normal human breast tissue, and studied NTS transcript on normal mammary glands, and on eight different human breast epithelial cells (HBEC) cultures.
  • HBEC human breast epithelial cells
  • FIG 1A left In order to evaluate if NTS gene is also regulated by estradiol in human breast, HBEC were exposed to estradiol.
  • figure 1A right an enhancement of NTS transcripts was observed. This effect was abolished when ICI 182780, a pure anti-estrogen, was added concomitantly to estradiol ( Figure 1A right ) suggesting that estrogen receptors participate in the NTS gene regulation in human breast tissue.
  • NTS expression was positively detected by immunohistochemistry in 19 (76%) biopsies of normal breast tissues from 25 premenopausal women.
  • the lobular structures were labeled with a more intense staining than the duct structures.
  • IDCs invasive ductal breast carcinomas
  • NTS transcript Five patients exhibited a very strong expression of NTS transcript ( Figure 2B , lane 2-6) and four others displayed a weaker expression ( Figure 2B , lane 7-9 and 11). No correlation was observed with prognosis factors and disease progression (tumor size, grade, number of invaded nodes, recurrence, and death) with NTS expression, neither in the ductal nor in the invasive components (Table 2). The only correlation found, was between PR and NTS expression in the invasive component. NTS is neither a marker nor associated with tumor progression in breast cancer.
  • NTSR1 staining in IDCs showed that NTSR1 expression was spread throughout many tumor cells in the invasive and ductal components. The labeling was granular and mostly cytosolic. In the invasive component of studied IDCs, the majority exhibited a high proportion of NTSR1 positive cells (from 50 to 100 %). We hypothesized that the deleterious effects of NTS should occur in tumors containing a very high proportion of NTSR1 expressing cells. We focused on the 35% of patients in which 80% or more of the tumor cells expressed NTSR1. Expression of NTSR1 was verified by RT-PCR on frozen tissues from 11 patients. As shown in Figure 2B , three patients expressed NTSR1 (lane 3, 6, 9) with two showing a very high amplicon amount ( Figure 2B lane 6, 9).
  • NTS-h hormone dependent breast cancer cells
  • NTS-1 hormone dependent breast cancer cells
  • NTS-h Two clones were selected with differential expression of NTS based on the amount of NTS transcript, NTS-h with high expression of NTS, NTS-1 with low expression of NTS
  • Expression of NTS did not change the expression of the steroid receptors, ER alpha and PR ( Figure 4A ).
  • the NTS expressing clones were still responsive to hormonal treatment estradiol and progesterone (data not shown).
  • no difference in cell proliferation rate was detected between wild type cells and NTS-h. Nevertheless, when MCF-7 and NTS-h cells were xenografted into nude mice, only NTS-h cells induced tumors.
  • NTSR1 expression is an early event of cell transformation, because of the resulting NTSR1 promoter activation by the Wnt/( ⁇ -catenin pathway ( Souaze et al. (2006) carcinogenesis 27:708-716 ).
  • NTSR1 is highly expressed ( ⁇ 80%) in 35% of the patients with a granular labeling mostly cytosolic suggesting an intense receptor endocytosis.
  • NTS cells Experiments using ectopically expressing NTS cells confirm this hypothesis. As the expression of steroid receptors was not affected by NTS in these cell lines, only cells highly expressing NTS were able to develop tumors when xenografted in mice without estradiol supplementation. Tumor growth is absent in wild type MCF-7 cells in these conditions whereas in NTS expressing cells, tumors were observed with a slow process ( ⁇ 6 months). Tumor formation was also observed in MCF-7 cells expressing NTS, when cells were injected in the mammary gland and the mice treated daily with estradiol. Under these conditions, tumor growth is a faster process showing 350 mg tumors after 2 months of growth (data not shown).
  • NTS/NTSR1 as a contributor to breast cancer progression.
  • These findings support the therapeutic potential of NTS/NTSR1 inhibition or drug cellular targeting through NTSR1 in advanced stages of human breast cancers. Imaging experiments strongly advance the concept of using NTS analogues for early and late detection of human breast tumors and its metastatic site expressing NTSR1.
  • NTSR1 goat polyclonal antibody C-20 Santa Cruz USA
  • NTS rabbit antibody NA1230 Biomol, USA
  • ER- ⁇ monoclonal antibody Santa Cruz
  • PR monoclonal antibody Santa Cruz
  • Immunostaining was carried out on deparaffinized sections using the streptavidin biotin peroxidase complex method as described previously by Souazé et al ( Souaze et al (2006) Cancer Res. 66:6243-6249 ). All slides were counterstained with hematoxylin.
  • a semi-quantitative estimation of the number of positive cells was performed by counting 1 000 reactive and non-reactive cells in ten successive fields at the original 200 X magnification.
  • HBEC normal human breast epithelial cells
  • RNA extraction was performed on 1 ⁇ g of total RNA using a specific NTSR1 primer (5'-GCTGACGTAGAAGAG-3' SEQ ID NO:3) or 50 pmol of oligo dT and oligo dN.
  • NTSR1 primer 5'-GCTGACGTAGAAGAG-3' SEQ ID NO:3
  • the PCR amplification was performed on a 1:5 v/v of the RT reaction using 25 pmol of each primer 5'-CGTGGAGCTGTACAACTTCA-3' SEQ ID NO:4 and 5'-CAGCCAGCAGACCACAAAGG-3' SEQ ID NO:5 for NTSR1, and 5'-AAGCACATGTTCCCTCTT-3' SEQ ID NO:6 and 5'-CATACAGCTGCCGTTTCAGA-3' SEQ ID NO:7 for NTS, and 1 unit of Taq polymerase (Applied Biosystems, Courtaboeuf, France).
  • the amplification profile consisted of denaturation at 94°C for 30s, annealing at 57°C for 45s, and extension at 72°C for 45s.
  • the PCR cycle were preceded by denaturation at 95°C for 15 min and were followed by a final extension at 72°C for 7 min.
  • HBEC HBEC were synchronized for 40h in Ham F10 phenol red free medium containing 20 ⁇ M lovastatin. Synchronization was stopped by adding 2mM mevalonate to the hormone-containing medium. Subsequently, cells were treated 48h in a phenol red free medium containing 5% of compatible human serum with 10nM estradiol (E2) with or without 1 ⁇ M ICI 182780.
  • MCF-7 cells were transfected by NTS coding sequence expressing vector. Stable clones were obtained using geneticin antibiotic selection. Two clones were chosen with differential NTS expression, NTS-h with high expression, and NTS-1 with low expression. 3 million cells with either MCF-7 or NTS-h were injected subcutaneously into the flank of nude mice. Only mice xenografted with NTS-h cells developed tumors over long periods, 9 months for the experiments presented here.

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Claims (5)

  1. Verfahren zur Bestimmung der Prognose bei einem Subjekt, das an Brustkrebs leidet, umfassend den Schritt der Bestimmung des Expressionsniveaus des Neurotensin-Rezeptors 1 (NTRS1) in Brustkrebszellen, die von dem Subjekt erhalten wurden, wobei eine hohe NTRS1-Expression mit einer schlechteren Prognose assoziiert ist.
  2. Verfahren nach Anspruch 1, wobei die NTSR1-Expression gemessen wird durch RT-PCR oder Immunochemie, die auf der Probe, die durch eine Biopsie erhalten wurde, ausgeführt wird.
  3. Verfahren nach Anspruch 1 oder 2, wobei der Krebs ein invasiver Krebs ist.
  4. Verfahren nach Anspruch 1 oder 2, wobei der Krebs ein in situ-Krebs ist.
  5. Verfahren nach einem der Ansprüche 1-4, wobei das Verfahren eingesetzt wird, um das Risiko des Wiederauftretens bei einem Subjekt, das chirurgisch behandelt worden ist, zu bewerten.
EP10700222.2A 2009-01-07 2010-01-05 Verfahren zur behandlung, prognosebeurteilung und erkennung von brustkrebs Active EP2374003B1 (de)

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EP10700222.2A EP2374003B1 (de) 2009-01-07 2010-01-05 Verfahren zur behandlung, prognosebeurteilung und erkennung von brustkrebs
PCT/EP2010/050044 WO2010079158A1 (en) 2009-01-07 2010-01-05 Methods for the treatment, the prognostic assessment and the detection of breast cancer

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CN103308689B (zh) * 2012-03-08 2017-04-12 思芬构技术有限公司 用于预测雌性对象中患上癌症的风险或诊断癌症的方法
CN103308670B (zh) 2012-03-08 2017-06-09 思芬构技术有限公司 用于预测对象患糖尿病和/或代谢综合征的风险的方法
CN103308673B (zh) 2012-03-08 2017-05-31 思芬构技术有限公司 用于预测雌性对象中发生心血管事件的风险的方法
CN110221071A (zh) * 2012-10-02 2019-09-10 斯弗因高泰克有限公司 预测女性对象患癌症风险或诊断其癌症的方法
EP2740726A1 (de) * 2012-12-07 2014-06-11 3B Pharmaceuticals GmbH Neurotensin-Rezeptorligande
WO2015158809A1 (en) * 2014-04-17 2015-10-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of cancer
US10077303B2 (en) * 2014-06-02 2018-09-18 Inserm (Institut National De La Sante Et De La Recherche Medicale) Anti-neurotensin antibodies and uses thereof
WO2016189091A1 (en) * 2015-05-26 2016-12-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions (ntsr1 inhibitors) for the treatment of hepatocellular carcinomas
WO2017012961A1 (en) * 2015-07-17 2017-01-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the prognosis and treatment of endometrial carcinoma
US20220048995A1 (en) * 2018-09-10 2022-02-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of an inhibitor of ntsr1 activation or expression for preventing weight loss, muscle loss, and protein blood level decrease in subjects in need thereof
US12091454B2 (en) 2022-12-28 2024-09-17 Development Center For Biotechnology Humanized anti-human neurotensin receptor 1 antibodies and their uses

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